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Development of TGF-β signalling inhibitors for cancer therapy

Key Points

  • When acting as a tumour suppressor, transforming growth factor-β (TGF-β) can potently inhibit the growth of endothelial, epithelial and haematopoietic cells. However, as the tumour evolves, the cells become refractory to TGF-β-mediated growth inhibition and begin to overexpress TGF-β, creating a favourable micro-environment for further growth and invasion of the tumour. The secretion of TGF-β by tumour cells also suppresses the immune response to the tumour and allows its further progression.

  • Several studies have shown the potential of targeting TGF-β signalling and, despite earlier predictions of severe toxicity, neutralizing antibodies to TGF-β have been well tolerated and have potent antimetastatic activity. Large-molecule antagonists of TGF-β signalling, such as pan-neutralizing antibodies, TGF-β ligand isoform-specific antibodies and antisense molecules targeting TGF-β mRNA, are most advanced in clinical development, predominantly for fibrosis but with some therapies for cancer now beginning trials.

  • Small-molecule drug discovery efforts have mainly focused on the type I TGF-β receptor kinase, and most known TGF-β inhibitors have several common structural features, including a crucial 'warhead' group that contains a hydrogen-bond acceptor. Several companies have reported the efficacy of small-molecule inhibitors at inhibiting proliferative and immunosuppressive effects of TGF-β in cell-based assays and cancer models, and several candidates are now moving into trials for advanced cancer.

  • The contrasting roles of TGF-β and the changing selectivity profile of TGF-β inhibitors with their increasing concentrations highlight the importance of developing targeted therapies for well-defined patient populations in which the tumour-promoting activity of TGF-β predominates. Preclinical pharmacokinetic and pharmacodynamic studies using functional biomarkers will aid progress towards this goal.

Abstract

The transforming growth factor-β (TGF-β) superfamily of ligands has a pivotal role in the regulation of a wide variety of physiological processes from development to pathogenesis. Since the discovery of the prototypic member, TGF-β, almost 20 years ago, there have been tremendous advances in our understanding of the complex biology of this superfamily. Deregulation of TGF-β has been implicated in the pathogenesis of a variety of diseases, including cancer and fibrosis. Here we present the rationale for evaluating TGF-β signalling inhibitors as cancer therapeutics, the structures of small-molecule inhibitors that are in development and the targeted drug discovery model that is being applied to their development.

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Figure 1: Transforming growth factor-β signalling in tumour cells and points of therapeutic intervention.
Figure 2: The role of transforming growth factor-β in the tumour micro-environment.
Figure 3: Small-molecule inhibitors of the transforming growth factor-β kinase domain.
Figure 4: Co-crystallization data for TβRI kinase inhibitors.
Figure 5: In vivo pharmacokinetic and pharmacodynamic drug discovery model for transforming growth factor-β receptor I kinase inhibitors.

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Acknowledgements

The authors wish to thank R. Gaynor, H. Pearce and J. Starling for helpful discussions and critical review of the manuscript, and S. Balsbaugh for excellent technical assistance.

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Correspondence to Jonathan M. Yingling.

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All of the authors of this paper are employees of Eli Lilly & Co., which researches kinase inhibitors as potential therapeutic agents.

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DATABASES

Entrez Gene

ALK2

ALK4

ALK5

ALK7

BMP4

BMP7

CDK2

CDK4

c-Myc

CTGF

EGFR

ERBB2

JNK

KDR

MAPK14

PAI1

RAC2

SMAD2

SMAD3

SMAD4

SNAIL

TGF-β1

TGF-β2

TGF-β3

TGFBR2

TLP

TWIST

VEGF

Glossary

SMADS

A family of homologous proteins that mediate TGF-β superfamily signal transduction. Some SMADs are transcription factors that are phosphorylated and translocate into the nucleus in response to TGFβ.

EPITHELIAL–MESENCHYMAL TRANSITION

(EMT). Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

FC:SOLUBLE TYPE II RECEPTOR

A chimeric protein of the murine constant fragment (Fc) immunoglobulin G and the extracellular domain of the TGF-β type II receptor.

SYNGENEIC

Genetically identical; for example, a fully inbred strain of mouse.

FLOXED

Refers to a DNA construct in which a gene or gene segment is flanked by loxP sites that are recognized by Cre recombinase, therefore allowing the context-specific excision of the gene segment situated between the loxP sites.

GENETIC MODIFIER SCREEN

Model organisms with a particular disease phenotype are crossed with organisms that carry other mutations, which allows screening for mutations in other genes that modify (either enhance or suppress) the severity of the original disease phenotype. In cells this is typically accomplished by retroviral infection of a cDNA library.

BIGENIC MICE

Mice that have had two different genes modified.

THERAPEUTIC INDEX

The ratio of the dose required to produce toxic or lethal effects to the dose required to produce a non-adverse or therapeutic response.

PHAGE-DISPLAY TECHNOLOGY

A screen for proteins that works by integrating several genes from a gene bank into phage to create phage-display libraries. The genes are expressed in an immunologically accessible form on the surface of the virion. The libraries can be used to screen for protein interactions, and hits can be affinity purified using antibodies.

SCLERODERMA

A pathological thickening and hardening of the skin.

CONVECTION-ENHANCED DELIVERY

A technique that uses small differences in pressure to make infused molecules flow through solid tissue, allowing high-molecular-mass molecules to penetrate the brain stem.

ANAPLASTIC ASTROCYTOMA

A diffusely infiltrating astrocytoma with marked proliferative potential that arises from low-grade astrocytomas and has an intrinsic tendency for malignant progression to glioblastoma.

ORTHOTOPIC TUMOUR MODEL

A tumour that is transplanted into a model organism in the same position as it would normally occur in humans.

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Yingling, J., Blanchard, K. & Sawyer, J. Development of TGF-β signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3, 1011–1022 (2004). https://doi.org/10.1038/nrd1580

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